Method for the preparation of dfflydro-



Mann,

United States Patent METIIOD FOR THE PREPARATION OF DIHYDRO-TESTOSTERONE AND ITS ESTERS Alberto .Ercoli' and Pietro de Ruggieri,Milan, Italy, assiguors to Francesco Vismara'Societa per Azioni, Como,Italy, a corporation of Italy, and Alberto Ercoli, Milan, Italy NoDrawing. Application January 15, 1954,

. Serial No. 404,377

Claims. ((31. 260-5914 tained is then submitted to the combined-actionof an aliphatic alcohol and an alkali metal, in order to obtain an enolether or a ketal of testosterone from which finally the testosterone andits esters may be obtained. The applicants have now discovered that aprocess perfectly analogous is suitable also in the preparation ofdihydrogenated (in position 4-5) testosterone, or androstanl7}8-ol-3-one (VI), commonly known under the name of 4-dihydro-testosterone.

Inthis case the necessary intermediate is the androstan- The'presentinvention relates to the manufacture of this'intermediate (III) and itsfurther transformation into dihydrotestosterone (VI) or in its esters(VIII: Where R-CO:adicaloforganic acid according to a series .ofreactions which are substantially analogous to those described in theabove mentioned application.

4 The process according to the invention may be illustrated by thescheme represented on the last page hereof In practicing containing theformulas from .I to VIII. our invention we proceed as follows:

- The cyanohydrin of androstan-Se-ol-l7-one orandrostan-17-cyan-3B,l7-diol, mixture of two 17-epimers .(II)-'which maybeeasily prepared from androstanproduct in its turnby treatment withsodium and propyl alcohol is transformed into a solution ofS-diethyl-ketal of 4-dihydrotestosterone (V). The propyl alcoholsolution containing the new intermediate, by acidification in ithe hotwith dilute hydrochloric acid, yields directly the l4-dihydrotestosterone (VI). also'be isolated by simple dilution of thepropyl alcohol solution and the esters of the 4-dihydrotestosterone(VIII) may be obtained by acylation of the group OH in position 17, withintermediate formation of esters of 3- diethyl-ketal of .Theintermediate V may the 4-dihydrotestosterone (VII): after-- to thesolution.

2,734,066 Patented Feb. 7, 1955 hydrolysis the esters of4-dihydrotestosterone (VIII) are obtained.

Instead of using the cyanohydrin of'androstan-BB-ol- -l7-one, thecyanohydrin of andro stan-3a-ol-l7-one may be also employed which, bychromic oxidation, yields the same intermediate III,

Instead of using ethyl orthoformate, other acetalysing agents may bealso employed as for instance other esters of orthoformic acid, alcohols(e. g., benzyl alcohol), glycols (e. g., ethylene glycol) always inthe'presence of catalysers of acid nature; intermediate productscontaining in position '3 the ketal groups corresponding to theacetalysing agents employed, are thus prepared:

and similar products) From androstan-3 8-ol-l7-one (I) as startingmaterial or directly from the crude oxidation products of thedihydrocholesterol, the corresponding cyanohydrin (II) is prepared byaction of acetone cyanohydrin (according to the French Patent No.1,058,454 dated November 4,

The cyanohydrin (II) (mixture of two l7-epimers:androstan-17-a-cyan-3fi-l7p-diol and androstan-17B-cyan- 3fl-17a-diol,M. P. dec. about 170 C.) is used in the crude state, simply well washedwith petrol ether and dried in the vacuum.

10 g. of this cyanohydrin are suspended in a mixture of cc. of ethylenechloride and 200 cc. of acetic acid. Then a solution of 3 g. of chromicanhydride in 60 cc. of acetic acid at is slowly added at the temperatureof 15 C. during 15 minutes. The mixture is maintained in agitation.After 24 hours, ether and water are added The ethereal layer, whichseparates off, is repeatedly washed with water, dried over sodiumsulfate and evaporated in the vacuum. A solid crystalline resi? due ofabout 8.85 g. is obtained which, recrystallised from ether, yields 8.35g. of androstan-17-cyan-l7-ol-3- one (III) (mixture of two possiblel7-epimers, M. P. 207 C. dec.). This intermediate will be calledandrostandione-17-monocyanohydrin hereinafter. I

8.35 g. of androstandione-l7-monocyanohydrin are suspended in cc. ofbenzene, then 55 cc. of benzene are distilled in order to eliminatemoisture. The temperature is brought to 65 C. and, while maintaining it,9.5 g. of ethyl orthoformate, 5 cc. of absolute ethyl alcohol and 0.43cc. of a 7% hydrogen chloride solution in absolute ethyl alcohol (0.03g. of HCl) are added. After 15 minutes all the original product goesinto solution and a new crystallisation begins. After another 45 minutesat 65 'C., 0.075 cc. of pyridine are added and the solution isevaporated in the vacuum to dryness; a residue of 8.9 g. of crude3-diethyl-ketal of androstandione-17- monocyanohydrin (IV) is obtained.

This residue is dissolved in 230 cc. of propyl alcohol and rea ed on t eboilin Wate at with 9 9i 594m?! in small pieces for about 30 minutes.

When the rea tio ashie etl he m xture hi h n cont in the ethYl-lteta oaadroetaaw l-- e (V), i aci ified o redo a th 2. N h teshl i q sidanddiluted with boiling water. Most of the propyl alcohol i elim na ed bydisti la ion at q lted @mswm nd en, by co lin an a lowi t9 re t erstella ie of 6.9 g f -di ydr es os emtie (VI) M- P- l l C. is obtained.

Example .2

Th r action is carried out with the same pr eedut as in Example 1 usingthe same starting materials in the same quantities until the treatmentwith propyl alcohol and sodium of the 3-diethyl-ketal ofandrostandione-l7- monocyanohydrin (IV), The solution in propyl alcoholso obtained is diluted with water and allowed to crystallise. Theseparation of about 8 g. of crude 3- diethyl-ketal ofandrostan-l7fi-ol-3-one (V) M. P. 120-138 C. is obtained. The product isdissolved in 75 cc. of pyridine and acetylated'at room temperature byadding 35 cc. of acetic anhydride. After a night the excess of aceticanhydride is decomposed by dilution with water and the acetyl derivativeis extracted with ether. The ether, washed with dilute sodium carbonatend w er, a t r s cc tion and vW pQ et O g es a residue of 3-diethyl-lcetal of 17fi acetoxy-androstan-3- one (VII where: R=CH3) inacrudestate. This product is dissolved in 35cc. of acetone andthesolution is heated with reflux for 10 minutes with addition of Q15cc. of concentrated hydrochloric acid. The mixture is then diluted withwater and allowed to cool: the product which separates off, aftercrystallisation-from petrol ether, yields about 7 go d yd ot t t i neaestat 1 W1 R=CH3) M. P. 153156 C.

Similarly the other esters of dihydrotestosterone are prepared.

We claim:

1. A process for the preparation of 4-dihydrotestosterone whichcomprises oxidizing with chromic acid the cyanohydrin ofandrostan-3-ol-17-one to form androstana l7-cyan-l7-ol-3-one; treatingthis intermediate in the presence of an acid catalyst with anacetalysing agent, selected from the group consisting of QIlIhOfQllIliQ! acid esters, aryl alcohols and aliphatic glycols; therebyobtaining as a sec ond interme'diate'a 3-ketal derivative of the androstan17-cyan-17-ol-3-one;subjecting the second intermediate compound to the"concomitant aeti'onmft a boiling aliphatic alcohol of the seriescontaining to carbon atoms and an alkali metal to eliminate the CN groupin 17-position and to form in the alkaline alcoholic solution a 3-ketalderivative of 4-dihydrotestosterone, acidifying the said boilingalkaline alcoholic solution with a mineral acid and diluting the samewith boiling water to obtain 4-dihydrotestosterone.

2. A process as defined inclaiml wherein the acetalysing agent isethyliorthoforrnat'e." process as defined in'claim 1 wherein the acetalysiugagent is benzyl alcohol. 4."Aprloce:ss as defined-"in claim 1 whereinthe acetalysing agent is ethylene glycol.

5. A process as defined 'incl'aim 1 wherein an acid of the groupconsisting of mineral and aromatic sulfonic acids is employed ascatalyst in the" acetalysatior'i'jstep.

A process its definedin claim 1 wherein the acetalysation 'stepiscarried but in presence 'ofa 'solv'ent 'of the series of benzene and its'methyl'homologuels," and water formed inthe 'acetalys'ation isrem'mze'd b annua tion of the same solvent forming 'an azeotrop icmixture therewith. I 6. A process as defined in claim 1 wherein theacetalysation step is carried out in presencecf'asolvent of cyanohydrinof androstan-3 ol 17-onejtdforni andrdstan- 17- cyan-17-ol 3-on'e;treating this intermediate'in the presence of an acid catalyst withanacetalysing agent selected from the group" consisting oforthofo'riiiicacid estersparyl alcohols and aliphatic glycols,ltlielebyobtaim ing as a second intermediate a 3-glycol ketalderivative" of 4- dihydrotestoisterone; diluting the said "alkalinealcoholic solution with water to precipitate and isolate"th 3-kelta'lderivative of 4-dihydrotestosterone'; acylating the" latter in the driedstate at the OH group in 17-position with ai1 organic carboxylic acidanhydr'ide of the series of aliphatic acid anhydrides corresponding tothe acids con- Itaining from 2 to 6 carbon 'atorns'Qinthe' presence ofpyridine, to obtain a 17-acylesterof the 3-ketal derivative of4-dihydrotestoster one; ,hy drolysin g the"3- ketal function of thelatter by gentle boiling in""aceton'e ihithe presence of traces ofmineral acid and water' to obtain the corresponding 4-dihydrotestosterone-l7-acyl ester'l" 8. A process as defined in claim 7wherin theacetalysing agent is ethyl orthoformate. 9.'A process asdefinediniclair'n 7 wherein the acetalysing agent is benzyl' alcohol; 10. Aprocess as defined in claim 7 wherein the acetalysing agent is ethyleneglycol.

ReferencesVCited in the file of this patent UNITED STATES PATENTSMiescher .Oct. .28, .1941 Westphal Sept. 1,1942

FOREIGN PATENTS Switzerland Mar. .3, 1941

1. A PROCESS FOR THE PREPARATION OF 4-DIHYDROTESTOSTERONE WHICHCOMPRISES OXIDIZING WITH CHROMIC ACID THE CYANOHYDRIN OFANDROSTAN-3-OL-17-ONE TO FORM ANDROSTAN17-CYAN-17-OL-3-ONE; TREATINGTHIS INTERMEDIATE IN THE PRESENCE OF AN ACID CATALYST WITH ANACETALYSING AGENT, SELECTED FROM THE GROUP CONSISTING OF ORTHOFORMICACID ESTERS, ARYL ALCOHOLS AND ALIPHATIC GLYCOLS, THEREBY OBTAINING AS ASECOND INTERMEDIATE A 3-KETAL DERIVATIVE OF THEANDROSTAN-17-CYAN-17-OL-3-ONE; SUBJECTING THE SECOND INTERMEDIATECOMPOUND TO THE CNCOMITANT ACTION OF A BOILING ALIPHATIC ALCOHOL OF THESERIES CONTAINING 2 TO 5 CARBON ATOMS AND AN ALKALI METAL TO ELIMINATETHE CN GROUP IN 17-POSITION AND TO FORM IN THE ALKALINE ALCOHLICSOLUTION A 3-KETAL DERIVATIVE OF 4-DIHYDROTESTOSTERONE, ACIDIFYING THESAID BOILING ALKALINE ALCOHOLIC SOLUTION WITH A MINERAL ACID ANDDILUTING THE SAME WITH BOILING WATER TO OBTAIN 4-DIHYDROTESTOSTERONE.